As Rods Go, So Go the Cones

Rod cells in our eyes help us see in dim light. They also ensure that the cones, the other light-sensitive cells we depend on for vision, get enough food, a new study reveals. The findings may shed light on a common cause of blindness.

Approximately 100,000 people in the United States have retinitis pigmentosa, an incurable inherited retinal disease that leads to blindness. More than 40 genes can contribute to the disease, often by damaging important proteins in retinal cells. The disease's initial symptom, night-vision loss, appears when rods start dying off. This attrition usually begins in childhood, and though it's inconvenient, most people get by with their cones--the photoreceptive cells that work in bright light. But by the time affected people reach adulthood, the cones begin dying, too, ultimately resulting in total blindness. This has confounded scientists, because the faulty genes aren't active in the cones, only in the rods.

To crack this mystery, biologist Constance Cepko of Harvard University and her colleague Claudio Punzo, a postdoctoral researcher, first evaluated previous theories. Some researchers thought that when the rods died, they produced a toxin that killed the cones. Others hypothesized that because rods use lots of oxygen in the retina, their death might leave behind a large amount of oxygen that overloads and damages the remaining cones. But neither of these seemed to fit the pattern, Cepko says, so he and Punzo decided to look for a new explanation.

The researchers measured gene activity in four different strains of mice with defective rod cells. They discovered more than 200 genes that are switched on at about the same time the cones started dying, many of them related to cell metabolism.

"That was our first clue that perhaps the cells weren't getting enough nutrients," Cepko says. Several of these genes were tied to a protein known as the mammalian target of rapamycin, or mTOR, which lets the cell know whether it has enough nutrients--especially glucose. But if starvation lasts long enough, mTOR directs the cell to digest itself. That's exactly what the cones were doing.

To determine whether a glucose drop-off was killing the cones, the researchers abdominally injected some of the mice with insulin to increase their glucose levels. The shots did cause the cones to hang on a little longer, but they nonetheless died a few weeks later.

Cepko and Punzo think the cones might starve because of the retina's crumbling architecture. A thin layer of cells, known as the retinal pigment epithelium (RPE), covers the rods and cones like a circus tent and delivers their nutrients. Rods significantly outnumber cones in the retina, so when they die, most of the RPEs' "tent poles" die with them. The tent collapses, the cones lose their nutrient connection, and they slowly starve. The study is published online this week in Nature Neuroscience.

"I think it's very exciting," says Rafael Caruso, an ophthalmologist with the U.S. National Eye Institute in Bethesda, Maryland. "It's a new approach to the problem." Caruso says that the researchers "make a pretty persuasive case for their conclusions," especially because the same mutations in the tested mice are also found in humans.

Unfortunately, both Cepko and Caruso agree that the finding does little for researchers looking for treatments. But it does suggest a new framework for thinking about the problem. By exploring different ways to get nutrients into the cones, Cepko says, researchers might one day be able to help people with retinitis pigmentosa keep their daytime vision for a longer period of time.